Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

Interleukin-2 (IL-2; aldesleukin [Proleukin: Chiron, Emeryville, CA]) is a cytokine with the following immune-modulating effects: enhancement of lymphocyte mitogenesis and cytotoxicity, induction of lymphocyte-activated (LAK) cells and natural killer (NK) cells, and induction of interferon gamma production. Labeled indications approved by the U.S. Food and Drug Administration (FDA) include the treatment of metastatic renal cell carcinoma and metastatic malignant melanoma. In addition, other oncologic applications of IL-2 monotherapy are being actively investigated, principally as a technique to maintain remission or eliminate minimal residual disease in patients with a variety of malignancies, including most prominently leukemias, but also including lymphomas and other solid tumors such as neuroblastoma and breast cancer. IL-2 has also been used post-autologous bone marrow transplantation as an immunotherapeutic technique to maintain remission and reduce the relapse rate. IL-2 has also been investigated as a component of a variety of combination therapies, for example in combination with interferon alpha in the treatment of metastatic renal cell cancer and metastatic melanoma. Combination therapy is not addressed in this policy.

Note: Interleukin-2 may be used as component of adoptive immunotherapy. Adoptive immunotherapy is addressed separately in policy No. 8.01.01.

Note: Interleukin-2 has also been investigated as a treatment of HIV-infected individuals. This application is considered separately in policy No. 8.01.41.

Note:Interleukin-2 may be used as a component of a melanoma vaccine. Melanoma vaccines are considered as part of policy No. 2.03.04, Tumor Vaccines.

Policy

IL-2 monotherapy may be considered medically necessary in the treatment of metastatic renal cell carcinoma and metastatic melanoma.

Perilymphatic injection of IL-2 may be considered medically necessary in patients with resectable, non-metastatic squamous cell cancer of the oral cavity and oropharynx (see Policy Guidelines).

IL-2 in combination with chemotherapy or in combination with interferon alfa is considered investigational as a treatment of metastatic melanoma and renal cell cancer.

IL-2 is considered investigational as a therapy to maintain remission after high-dose chemotherapy for a variety of malignancies, including multiple myeloma, leukemia, lymphoma, multiple myeloma, or breast cancer.

Other oncologic applications of IL-2 monotherapy are considered investigational, including but not limited to the following:

colorectal cancer;

hepatocellular carcinoma;

small-cell and non-small-cell lung cancers;

acute leukemia;

myelodysplastic syndromes;

multiple myeloma;

non-Hodgkin's and Hodgkin's lymphoma;

Ewing's sarcoma;

soft tissue sarcoma;

osteosarcoma;

bladder

brain

breast

esophagus

ovary

pancreas

prostate

small bowel

stomach

testes

thyroid

Policy Guidelines

General

IL-2 treatment protocols for metastatic melanoma and renal cancer vary in terms of dosages and duration of treatment. Higher dosages of intravenous (IV) IL-2 (at least 600,000 IU/8 hours) may require hospitalization to monitor for the capillary leak syndrome. Continuous infusion or subcutaneous IL-2 may be given on an outpatient basis.

Squamous cell cancer of the oral cavity and oropharynx

The policy statement regarding IL-2 therapy for patients with resectable malignancies of the oral cavity and oropharynx is based on the results of a randomized study that included the following protocol:

5000 U IL-2 was injected into the ipsilateral cervical lymph node chain for 10 days before surgery

Additional 5-day courses were given monthly in the residual ipsilateral lymph node chain for 1 year

Benefit Application

BlueCard/National Account Issues

State and federal mandates requiring coverage of FDA-approved drugs may supercede this policy.

For example, Medicare coverage policy on cancer-related drugs is proscribed by an amendment to the Social Security Act, which specifies sources of information that Medicare must consider in reviewing appropriateness of treatment. Medicare requires that a drug or biologic used in an anticancer chemotherapeutic regimen for a medically accepted indication is defined as:

a drug that has been approved by the FDA; and

the use is supported by 1 or more citations that are included (or approved for inclusion) in 1 or more of the following compendia: the American Hospital Formulary Service-Drug Information, the American Medical Association Drug Evaluations (note: no longer published), the U.S. Pharmacopoeia-Drug Information, and other authoritative compendia as identified by the Secretary, unless the Secretary has determined the use is not medically appropriate or the use is identified as not indicated in 1 or more such compendia, or

the carrier involved determines, based on guidance from the Secretary to carriers for determining accepted uses of drugs, that such use is medically accepted based on supportive clinical evidence in peer-reviewed medical literature appearing in publications that have been identified for purposes of this subclass by the Secretary

The Secretary may revise the list of compendia as is appropriate for identifying medically accepted indications for drugs.

Some plans may participate in voluntary programs offering coverage for patients participating in clinical trials of cancer chemotherapies, including IL-2, that have been approved by the National Institutes of Health (NIH).

Rationale

IL-2 Monotherapy for Metastatic Renal Cell Cancer

The product insert for Proleukin (Chiron, Emeryville, CA) summarizes clinical data used as part of the FDA-approval process. (1) In clinical studies of metastatic renal cell cancer, including 255 patients treated with single agent IL-2, there was a 15% response rate (including both complete and partial responses) with a median response duration of 54 months. In clinical studies of metastatic melanoma, including 270 patients, there was a 16% response rate with a median duration of 9 months. These results may be considered clinically significant given the failure of other chemotherapeutic approaches. The labeled indication recommends a dose schedule of a 15-minute short intravenous infusion at doses of 600,000 IU every 8 hours (referred to as “high dose”). This regimen requires hospitalization to monitor for toxicities, including the capillary leak syndrome. Other dose schedules (i.e., continuous or subcutaneous infusion) and combinations with other agents (i.e., interferon or other chemotherapeutic agents) have also been explored, both as a method to increase effectiveness and decrease toxicity. In 2003, Yang and colleagues reported the results of a trial that randomized 306 patients with metastatic renal cell cancer to receive 1 of 3 regimens of IL-2: 1) high-dose IV (720,000 U/kg) every 8 hours; 2) low-dose IV (72,000 U/kg ) IL-2 every 8 hours; or 3) low-dose daily subcutaneous IL-2. (2) There was a higher response rate in those receiving the high-dose regimen compared to either of the 2 low-dose regimens, but no difference in survival rates. Toxicities were also higher with the high-dose regimen. Clark and colleagues also reported on the results of a trial of IL-2, focusing on its use in the immediate postoperative period. (3) Patient selection criteria included resected locally advanced or metastatic renal cell cancer. Patients were randomized to receive either 1 course of high-dose IL-2 (600,000 U/kg every 8 hours) or observation. The trial was closed early when interim analysis concluded that the anticipated 30% improvement in the 2-year disease-free survival could not be achieved.

IL-2 Combination Therapy for Metastatic Renal Cell Cancer

Negrier and colleagues studied the role of a subcutaneous combination of subcutaneous IL-2 and interferon alfa with or without additional 5-FU in patients with metastatic renal cell cancer. (4) Therefore, this study examined the incremental effect of 5-FU, and did not examine whether or not combining IL-2 and interferon produced an incremental effect compared to either treatment alone. Overall survival in both arms was similar (53%). In addition, the response rate was 8.2%, considerably lower than the response rate seen in both preliminary phase II trials of subcutaneous IL-2 or in trials of IV IL-2, and suggesting that subcutaneous IL-2 may be inferior to IV IL-2. Two randomized studies were identified that compared the treatment outcomes of combined subcutaneous IL-2 and interferon alpha compared to treatment with tamoxifen alone. (5, 6) Therefore, these studies cannot answer the question of whether combined immunotherapy has any advantage over IL-2 monotherapy. While subcutaneous IL-2 therapy is associated with decreased complications compared to IV IL-2, the relative efficacy of the 2 routes of administration is unknown.

IL-2 Monotherapy for Metastatic Melanoma

The product insert for Proleukin (Chiron, Emeryville, CA) summarizes clinical data used as part of the FDA-approval process. A total of 270 patients with metastatic melanoma participated. Objective responses were seen in 16% of patients with 6% achieving complete remission. (1)

IL-2 Combination Therapy for Metastatic Melanoma

Several randomized studies were identified that reported no incremental benefit comparing interferon monotherapy to various combination therapies. For example, Rosenberg and colleagues reported on the results of a trial that randomized 102 patients with metastatic melanoma to receive chemotherapy (tamoxifen, cisplatin, dacarbazine) with or without additional IL-2 and interferon alfa (i.e., chemoimmunotherapy). (7) The addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The authors concluded that the use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized trials. Several other randomized trials, using different regimens of subcutaneous or intravenous IL-2, have reported similar disappointing results of chemoimmunotherapy, in part due to the toxicity of IL-2 and the lack of impact on overall survival. (8-11)

It is hoped that IL-2 therapy following high-dose chemotherapy and stem-cell transplant will eradicate the minimal residual disease that is presumably responsible for early relapses. It is hypothesized that IL-2 will stimulate host immune cells and increase the antigenicity of residual tumor cells. A large volume of literature has been published on these applications of IL-2, but the bulk of the literature consists of single institution case series in which there is no control group. In many instances, the outcomes focus on the effect of IL-2 on the numbers and function of natural killer (NK) cells. Many reports include patients with a variety of malignancies, including prominently leukemias, but also lymphomas and a variety of solid tumors including neuroblastoma and breast cancer. The success of immunotherapy is not uniform across malignancies, and thus data regarding IL-2 therapy must be evaluated separately for each indication. In addition, the dosage and route of administration of IL-2 vary among studies; frequently, IL-2 is included as a component of an immunomodulatory regimen that may also include alpha-interferon. In the post-bone marrow transplant setting, low-dose subcutaneous IL-2 is often used. This regimen has been found to be safe and well tolerated.

In 1995, Attal and colleagues reported on a randomized trial that studied the impact of IL-2 used after autologous bone marrow transplantation as a treatment of adult acute lymphoblastic leukemia. (12) A total of 60 patients were randomized to receive or not to receive IL-2 after autologous bone marrow transplantation. The probability of complete remission was similar in the 2 groups, leading the authors to conclude that IL-2 does not decrease the high relapse rate observed after bone marrow transplantation for adult ALL. Other studies have also suggested that IL-2 is not effective in the post-transplant setting for ALL (13,14) or have reported improved outcomes compared with historical controls. (15) Cortes and colleagues reported on a pilot study of IV IL-2 in 18 adult patients with acute myelogenous leukemia in first complete remission. (16) Compared to historical controls, there was a prolongation of the duration of complete remission in those receiving IL-2. These preliminary findings require further study in controlled trials. The authors concluded that the regimen was tolerable.

Resectable Squamous Cell Cancer of the Oral Cavity and Oropharynx

De Stefani and colleagues reported on the results of a trial that randomized 220 patients with resectable squamous cell cancer of the oral cavity and oropharynx to undergo surgery alone or surgery in conjunction with preoperative and postoperative injection of IL-2 into the perilymphatic tissue. (17) The group assigned to IL-2 therapy had a significantly improved length of disease-free survival and overall survival, and based on these results, this application of IL-2 may be considered medically necessary.

Ongoing Clinical Trials

A search of active clinical trials, as part of the National Cancer Institute’s Physician Data Query database (18) shows a continuing research interest in IL-2. A total of 75 trials are listed, many of them involving either adoptive immunotherapy or tumor vaccines, addressed in policy Nos. 8.01.01 and 2.03.04, respectively. Other oncology indications include several phase III studies of IL-2 as part of an immunotherapy regimen after high-dose chemotherapy and bone marrow transplant for either neuroblastoma, acute myeloid leukemia, myelodysplastic syndrome, non- Hodgkin’s lymphoma, or breast cancer. Phase III trials also include studies comparing the use of interferon alone to combined chemoimmunotherapy with IL-2 in patients with melanoma or renal cell carcinoma.

2006 Update

A search of the literature was performed for the period of 2003 through January 2006. No additional studies were identified that would prompt reconsideration of the policy statements; therefore, the policy is unchanged.

Injection or infusion of biological response modifier as an anti-neoplastic agent (anti-neoplastic immunotherapy)

ICD-9 Diagnosis

042

Human immunodeficiency virus (HIV) disease

172

Malignant melanoma of the skin

189

Malignant neoplasm of the kidney

V10.82

Malignant melanoma of the skin

V10.52

History of malignant neoplasm of kidney

HCPCS

J9015

Aldesleukin, per single use vial

Type of Service

Therapy

Place of Service

Inpatient/Outpatient

Index

Aldesleukin
IL-2 (Interleukin-2)
Interleukin-2 (IL-2)
Proleukin

Policy History

Date

Action

Reason

12/01/95

Add to Therapy section

New policy

11/01/98

Replace policy

Policy reviewed; new indications discussed

12/18/02

Replace policy

Policy revised; new indication for IL-2 for treatment of head and neck cancer; other policy statements unchanged. Rationale section expanded, references added. Policy no longer includes discussion of IL-2 for HIV infection; that indication is now addressed separately, in policy No. 8.01.41